Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder and the leading cause of dementia in the Western world. Postmortem, it is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles, and a profound gray matter loss. Neurofibrillary tangles are composed of an abnormally hyperphosphorylated intracellular protein called tau, tightly wound into paired helical filaments and thought to impact microtubule assembly and protein trafficking, resulting in the eventual demise of neuronal viability. The extracellular amyloid plaque deposits are composed of a proteinacious core of insoluble aggregated amyloid-beta (Abeta) peptide and have led to the foundation of the amyloid hypothesis. This hypothesis postulates that Abeta is one of the principal causative factors of neuronal death in the brains of Alzheimer's patients. With multiple drugs now moving through clinical development for the treatment of Alzheimer's disease, we will review current and future treatment strategies aimed at improving both the cognitive deficits associated with the disease, as well as more novel approaches that may potentially slow or halt the deadly neurodegenerative progression of the disease.

FIG. 1.

The neuropathological steps of Alzheimer’s disease.

FIG. 2.

The amyloid cascade hypothesis. The amyloid precursor protein APP is processed by β and γ-secretases via the amyloidogenic pathway to yield a variety of toxic Aβ-containing species, ultimately resulting in neuronal cell death. These amyloidogenic species can be degraded by a number of catabolic proteases such as neprilysin, IDE, and plasmin, thereby clearing Aβ and preventing cell death. The nonamyloidogenic pathway results from α-secretase cleavage within the Aβ sequence of APP.